Bioresorbable hydrogel compositions for implantable prostheses

ABSTRACT

Crosslinked compositions formed from water-insoluble copolymers are disclosed. These compositions are copolymers having a bioresorbable region, a hydrophilic region and at least two cross-linkable functional groups per polymer chain. Crosslinking of these polymers can be effected in solution in organic solvents or in solvent-free systems. If crosslinking occurs in a humid environment, a hydrogel will form. If crosslinking occurs in a non-humid environment, a xerogel will form which will form a hydrogel when exposed to a humid environment and the resulting crosslinked materials form hydrogels when exposed to humid environments. These hydrogels are useful as components in medical devices such as implantable prostheses. In addition, such hydrogels are useful as delivery vehicles for therapeutic agents and as scaffolding for tissue engineering applications.

This application is a continuation of application of Ser. No.09/395,725, filed on Sep. 14, 1999, now U.S. Pat. No. 6,316,522 which isa continuation-in-part of Ser. No. 09/243,379, filed on Feb. 1, 1999,now U.S. Pat. No. 6,028,164, which is a continuation of application Ser.No. 09/145,588, filed on Sep. 2, 1998, now U.S. Pat. No. 6,005,020 whichis a divisional of Ser. No. 08/914,130, filed on Aug. 18, 1997, now U.S.Pat. No. 5,854,382.

FIELD OF INVENTION

This invention relates generally to compositions useful as components ofmedical devices. Particularly, the present invention relates tocross-linkable compositions formed from a water-insoluble copolymerhaving a bioresorbable region, a hydrophilic region and at least twocross-linkable functional groups per polymer chain. More particularly,this invention relates to such compositions comprising an organicsolution. When crosslinked and exposed to a humid environment, thesecompositions form bioresorbable hydrogels. Furthermore, thesecompositions are useful as delivery vehicles for therapeutic agents.Processes for forming such hydrogels are also disclosed, as areprocesses for forming medical devices having such hydrogels incorporatedtherein.

BACKGROUND OF RELATED TECHNOLOGY

It is generally known to provide a porous material, such as animplantable prosthesis, with a biocompatible, biodegradable sealant orcoating composition which initially renders the porous materialsubstantially fluid-impermeable. Over time, such a sealant compositionis resorbed and the healing process naturally takes over the sealingfunction as tissue ingrowth encapsulates the prosthesis. Naturallyderived, as well as chemically synthesized, sealant compositions arewell-known.

An example of a medical device having a sealing means is described atcolumn 4, lines 38-55 of U.S. Pat. No. 5,843,160. Such sealing meanspreclude the egress of blood and prevent endoluminal leakage. A specificexample of a sealing ring or sleeve is set forth at column 11, lines10-36.

Natural materials, such as collagen and gelatin, have been widely usedon textile grafts. U.S. Pat. Nos. 4,842,575 and 5,034,265 to HoffmanJr., et al. disclose the use of collagen as a sealant composition forgrafts. More recently, co-owned and co-pending U.S. Ser. No. 08/713,801discloses the use of a hydrogel or sol-gel mixture of polysaccharidesfor rendering fluid-tight porous implantable devices. Such sealantcompositions are beneficial in that they are able to seal an implantabledevice without the need for chemical modification of the surface thereofand provide improved bioresorbability as the healing process occurs.Furthermore, fibrin, an insoluble protein formed during the bloodclotting process, has also been used as a sealant for porous implantabledevices.

The use of such biologically-derived sealant compositions, however,suffers from several drawbacks. One such drawback is the difficulty inproducing consistent coatings due to variations inherent in naturalmaterials. Another drawback is that the body might identify suchcompositions as foreign and mount an immune response thereto. Thus,biologically-based sealant compositions can cause inflammation, as wellas infection, at or around the site of implantation. This might lead tolife-threatening complications.

Accordingly, attempts have been made to design sealant systems fromchemically synthesized materials which are easy to manufacture, whichare easy to control the desired characteristics and qualities thereof,and which have less potential for causing adverse biological reactions.For example, U.S. Pat. No. 4,826,945 to Cohn et al. disclosessynthetically-produced resorbable block copolymers ofpoly(.alpha.-hydroxy-carboxylic acid)/poly(oxyalkylene) which are usedto make absorbable sutures, wound and burn dressings, and partially ortotally biodegradable vascular grafts. However, these copolymers are notcrosslinked. The poly(alkylene) segments of such bio-absorbablecopolymers are disclosed to be water-soluble so that the body canexcrete the degraded block copolymer compositions. See also, Younes, H.and Cohn, D., J Biomed. Mater. Res. 21, 1301-1316 (1987) and Cohn, D.and Younes, H., J Biomed. Mater. Res. 22, 993-1009 (1988). As set forthabove, these compositions are not crosslinked and, as a consequence, arerelatively quickly bio-absorbed. Moreover, these non-crosslinkedcompositions generally require the presence of crystalline segments toretain their structural integrity. As a result of such crystallinesegments, these compositions have limited utility as sealants forvascular grafts.

Furthermore, U.S. Pat. No. 4,438,253 to Casey et al. discloses tri-blockcopolymers produced from the transesterification of poly(glycolic acid)and a hydroxyl-ended poly(alkylene glycol). Such compositions aredisclosed for use as resorbable monofilament sutures. The flexibility ofsuch compositions is controlled by the incorporation of an aromaticorthocarbonate, such as tetra-p-tolyl orthocarbonate, into the copolymerstructure. The strength and flexibility which makes such a compositionuseful as a suture, however, does not necessarily make it appropriatefor use as a sealant for a porous implantable prosthesis. Moreover,these tri-block copolymers are substantially non-crosslinked. Thus,while these compositions are somewhat hydrophilic, they do not formhydrogels.

Accordingly, attempts have been made to engineer bio-compatible hydrogelcompositions whose integrity can be controlled through crosslinking. Forexample, U.S. Pat. Nos. 5,410,016 and 5,529,914 to Hubbell et al.disclose water-soluble systems which, when crosslinked, utilize blockcopolymers having a water-soluble central block segment sandwichedbetween two hydrolytically labile extensions. Such copolymers arefurther end-capped with photopolymerizable acrylate functionalities.When crosslinked, these systems become hydrogels. The water-solublecentral block of such copolymers can include poly(ethylene glycol),whereas the hydrolytically labile extensions can be apoly(.alpha.-hydroxy acid), such as polyglycolic acid or polylacticacid. See, Sawhney, A. S., Pathak, C. P., Hubbell, J. A., Macromolecules1993, 26, 581-587. See also, U.S. Pat. No. 5,854,382, disclosing anaqueous emulsion of water-insoluble copolymer which is crosslinked toform a hydrogel.

Furthermore, U.S. Pat. No. 5,202,413 to Spinu discloses biodegradablemulti-block copolymers having sequentially ordered blocks of polylactideand/or polyglycolide produced by ring-opening polymerization of lactideand/or glycolide onto either an oligomeric diol or a diamine residuefollowed by chain extension with a di-functional compound, such asdiisocyanate, diacylchloride, or dichlorosilane. The general structureof such a composition is R-(A-B-A-L).sub.x -A-B-A-R, where A is apolyhydroxy acid, such as polylactide, polyglycolide or a copolymerthereof, B is an oligomeric diol or diamine residue, L is a diacylresidue derived from an aromatic diacyl halide or diisocyanate, and R isH or an end-capping group, such as an acyl radical. A major differencebetween the compositions set forth in the Spinu '413 patent and thosedescribed by the Cohn references supra is that Spinu uses lactide blockswhereas Cohn uses lactic acid blocks. Furthermore, like the Cohncopolymers, the copolymers described in the Spinu '413 patent are notcross-linkable.

In general, all of the synthetic compositions set forth above describecopolymers having one or more segments which are water-soluble.Accordingly, many of the compositions described by these references areintended to be rapidly biodegraded by the body.

Thus, there is a need for water-insoluble, fully cross-linkablepolymeric materials which are easily synthesized and provide controlledbioresorption in vivo. Moreover, there is a need for improved,cost-efficient, synthetic sealant compositions for porous, implantableprostheses which are characterized by their ability to self-emulsify andform stable, low viscosity emulsions. There is a further need forsealant compositions which are quickly cured, exist as hydrogels in anaqueous environment, and which remain flexible while dehydrated withoutthe need for an external plasticizer. The present invention is directedto meeting these and other needs.

SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a process forforming a covalently crosslinked composition in an organic solvent. Thiscomposition includes a water-insoluble copolymer which has abioresorbable region, a hydrophilic region, and a plurality ofcross-linkable functional groups per polymer chain. Use of an organicsolution allows for a broader range of bioresorbable compositions to beused in the present invention than is possible where a substantiallyinorganic solvent alone is used. Individual uses for these compositionsare as polymeric substrates, as scaffolding for tissue engineering, oras therapeutic agent delivery systems.

In another aspect of the present invention, there is provided a medicaldevice which has, as at least one component thereof, a bioresorbablecomposition. This composition comprises a hydrogel formed from thecrosslinking of a polymer containing a bioresorbable region, ahydrophilic region, a plurality of cross-linkable functional groups,and, optionally, a crosslinking agent, in an organic solution.

In a further aspect of the present invention, there is provided aprocess for forming a hydrogel. This process comprises providing asolution of a water-insoluble copolymer in an organic solvent. Thewater-insoluble copolymer includes a bioresorbable region, a hydrophilicregion, a plurality of cross-linkable functional groups per polymerchain, and, optionally, a crosslinking agent. Crosslinking of thecopolymer results in formation of a xerogel. This xerogel will form ahydrogel when exposed to a humid environment.

In a further aspect of the present invention there is provided anotherprocess for forming a hydrogel. This process comprises providing asolution of the above-mentioned water-insoluble copolymer in a solventmixture comprised of a water-miscible organic solvent and water.Effecting a crosslinking reaction of the copolymer composition in thissolution directly forms the hydrogel.

In yet a further aspect of the present invention, there is provided aprocess for forming a device, particularly a medical device, coated witha hydrogel. The hydrogel is formed from an organic solution whichcomprises a water-insoluble copolymer having a bioresorbable region, ahydrophilic region, a plurality of cross-linkable functional groups perpolymer chain and, optionally, a crosslinking agent. This processcomprises applying the solution to the medical device, initiating acrosslinking reaction, subsequently removing the organic solvent, andexposing the resulting xerogel to a humid environment to form ahydrogel.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to covalently crosslinked compositionsformed from water-insoluble copolymers. The copolymers of the presentinvention include a bioresorbable region, a hydrophilic region, and aplurality of cross-linkable functional groups per polymer chain, and arepresent in an organic solution. Prior to being crosslinked, thewater-insoluble copolymer compositions are soluble in organic solventsor solvent mixtures containing water-miscible organic solvents andwater. Once crosslinked, such compositions form xerogels (dry gels) inthe absence of water, or hydrogels in the presence of water. Forpurposes of the present invention, xerogels are crosslinked compositionswhich, when exposed to a humid environment, form hydrogels. Hydrogels(also known as aquagels) are materials that are able to swell rapidly inexcess water and retail large volumes of water in their swollenstructures. Hydrogels do not dissolve in water and maintainthree-dimensional networks. They are usually made of hydrophilic polymermolecules which are crosslinked either by chemical bonds or by othercohesion forces such as ionic interaction, hydrogen bonding, orhydrophobic interaction. Hydrogels are elastic solids in the sense thatthere exists a remembered reference configuration to which the systemreturns even after being deformed for a very long time. (see Park et al,Biodegradable Hydrogels for Drug Delivery, Technomic Pub. Co., July1993). These definitions are provided for reference only, and are notmeant in any way to limit the materials to which these terms mightapply. Xerogels or hydrogels formed from the compositions of the presentinvention can be introduced to a porous material to form a medicaldevice.

Compositions of the present invention might also function as deliveryvehicles for therapeutic agents. The use of organic solvents permits therapid formation of various compositions containing water-insolubleadditives and other water-insoluble polymers. The use of organicsolvents makes it easier to incorporate certain pharmaceuticalsubstances, as these substances are generally soluble in organicsolvents. Additionally, organic solvents are easy to eliminate in themanufacturing process, simplifying the process of producing thecompositions of the present invention, as well as the process ofproducing medical devices associated with hydrogels formed by thepresent invention. Further, organic solvents permit faster crosslinkingof the polymer than will occur in the absence of organic solvents, andthe use of organic solvents avoids the quenching of free radicals bywater. Most additives, including other polymers, will be soluble inorganic solvents, thereby facilitating their inclusion in compositionsof the present invention.

The copolymers of the compositions of the present invention aremulti-block copolymers including, for example, di-block copolymers,tri-block copolymers, star copolymers, and the like. For purposes ofillustration only, a typical tri-block copolymer of the presentinvention may have the following general formula:

xABAx (I)

wherein A is the bioresorbable region, B is the hydrophilic region and xis the cross-linkable functional group. A specific example of acopolymer useful in the composition of the present invention has thefollowing chemical structure:

wherein x is from 10 to about 100 and y is from about 50 to about 500,so long as the composition remains substantially water-insoluble as awhole.

A more specific example of a copolymer useful in the composition of thepresent invention has the following chemical structure:

wherein the ratio of A to B is about 3:1, x is from about 10 to about100, and y is from about 50 to about 300, so long as the compositionremains substantially water-insoluble as a whole. wherein the ratio of Ato B is about 3:1, x is from about 10 to about 100, and y is from about50 to about 300, so long as the composition remains substantiallywater-insoluble as a whole.

One feature of the present invention is that the cross-linkablecopolymer composition is substantially water-insoluble. For purposes ofthe present invention, “water-insoluble” is intended to mean that thecopolymers of the present invention have water solubility in the rangeof about 0.0 gm/100 ml to about 0.5 gm/100 ml. A method for determiningthe water-solubility of copolymers of the present invention is set forthbelow in Example 5.

As set forth above, the water-insoluble copolymer of the composition ofthe present invention includes a bioresorbable region. For purposes ofthe present invention, the term “bioresorbable” means that this regionis capable of being metabolized or broken down and resorbed and/oreliminated through normal excretory routes in the body. Such metabolitesor break-down products should be substantially non-toxic to the body.

The bioresorbable region can be hydrophobic. In another aspect, thebioresorbable region can be designed to be hydrophilic so long as thecopolymer composition as a whole remains substantially water-insoluble.The relative proportions or ratios of the bioresorbable to thehydrophilic regions, respectively, as well as any functional groupscontained therein, are specifically selected to render the copolymercomposition substantially water-insoluble. Furthermore, whencrosslinked, these compositions are sufficiently hydrophilic to formhydrogels in aqueous environments. Such hydrogels, as set forth in moredetail below, can form a fluid-impermeable barrier when applied to aporous material, particularly a medical device. The specific ratio ofthe two regions of the block copolymer composition of the presentinvention will, of course, vary depending upon the intended applicationand will be affected by the desired physical properties of the resultinghydrogels, the site of implantation, and other factors. For example, thecomposition of the present invention remains substantiallywater-insoluble when the ratio of the hydrophilic region to thehydrophobic region to is from about 5:1 to about 1:5, on a weight basis.Additionally, the selected ratios will depend on the relativehydrophilicity and molecular weights of the biodegradable andhydrophilic compounds chosen.

The bioresorbable region of the copolymer used in a composition of thepresent invention can be designed to be hydrolytically and/orenzymatically cleavable. For purposes of the present invention,“hydrolytically cleavable” refers to the susceptibility of thecopolymer, particularly the bioresorbable region, to hydrolysis in wateror in a water-containing environment. Similarly, “enzymaticallycleavable”, as used herein, refers to the susceptibility of thecopolymer, particularly the bioresorbable region, to cleavage byendogenous or exogenous enzymes.

Based on the characteristics set forth above, a number of differentcompounds can comprise the bioresorbable region. The bioresorbableregion can include, without limitation, for example, poly(esters),poly(hydroxy acids), poly(lactones), poly(amides), poly(ester-amides),poly(amino acids), poly(anhydrides), poly(ortho-esters),poly(carbonates), poly(phosphazines), poly(thioesters), polysaccharidesand mixtures thereof Furthermore, the bioresorbable region can alsoinclude, for example, a poly(hydroxy) acid includingpoly(.alpha.-hydroxy) acids and poly(.beta.-hydroxy) acids. Suchpoly(hydroxy) acids include, for example, polylactic acid, polyglycolicacid, polycaproic acid, polybutyric acid, polyvaleric acid, andcopolymers and mixtures thereof.

The substantially water-insoluble copolymers of the present inventionform solutions in organic solvents and in solvent mixtures containingwater-miscible organic solvents and minor amounts of water. For thepurposes of the present invention, an organic solution of the copolymeris defined as the copolymer in an organic solvent or the copolymer in amixture of an organic solvent and up to about 50% water. Organicsolvents which can be used, for example, are ethanol, 1-propanol,butanol, diethyl ether, dichloromethane, chloroform, dimethyl formamide,dimethyl acetamide, hexamethylphosphoramide, and toluene. These solventsare exemplary only and are not meant to be limit in any manner thesolvents which may be used in the present invention. Another aspect ofthe present invention utilizes the copolymer in a liquid state withoutsolvent.

As set forth above, the copolymer of the composition of the presentinvention also includes a hydrophilic region. For purposes of thepresent invention, “hydrophilic” is used in the traditional sense of amaterial or substance having an affinity for water. Although thecopolymer contains a hydrophilic region, this region is designed and/orselected so that the copolymer composition, as a whole, remainssubstantially water-insoluble at all times.

When placed in vivo, the hydrophilic region can be processed intoexcretable and/or metabolizable fragments. Thus, the hydrophilic regioncan comprise, without limitation, for example, polyethers, polyalkyleneoxides, poly(vinyl pyrrolidine), poly(vinyl alcohol), poly(alkyloxazolines), polysaccharides, polypeptides, proteins, and copolymers andmixtures thereof. Furthermore, the hydrophilic region can also be, forexample, a poly(alkylene) oxide. Such poly(alkylene) oxides can include,for example, poly(ethylene) oxide, poly(propylene) oxide, and mixturesand copolymers thereof;

As set forth above, the composition of the present invention alsoincludes a plurality of cross-linkable functional groups. Anycross-linkable functional group can be included in the copolymer so longas the copolymer which includes the cross-linkable functional group iscapable of forming a hydrogel. Cross-linkable functional groups whichcan be used in the present invention include olefinically unsaturatedgroups. Suitable olefinically unsaturated functional groups are, withoutlimitation, for example, acrylates, methacrylates, butenoates, maleates,allyl ethers, allyl thioesters, and N-allyl carbamates.

The cross-linkable functional groups may be present at any point alongthe polymer chain of the present composition, so long as their locationdoes not interfere with the intended function thereof, as set forthabove. Furthermore, the cross-linkable functional groups may be presentin the polymer chain of the present invention in numbers greater thantwo, so long as the intended function of the present composition is notcompromised.

Preferably, at least two olefinically unsaturated functional groups arepresent on the polymer chain of the present composition. As set forthabove, the number of olefinically unsaturated functional groups presenton the polymer chain may be more than two, depending upon the particularapplication of the composition. Although the olefinically unsaturatedfunctional groups may be positioned anywhere on the polymer chain of thepresent composition, it is preferred that at least one olefinicallyunsaturated functional group be positioned at a terminus of the polymerchain. More preferably, an olefinically unsaturated group is positionedat both terminal ends of the polymer chain. Furthermore, as there are atleast two functional groups present in the copolymer composition, thefunctional groups contained therein may be the same or different.

Crosslinking of the polymer compositions of the present invention isaccomplished through the cross-linkable functional groups. Thesefunctional groups can be activated by a variety of crosslinking means inorder to crosslink the copolymer composition. These crosslinking meansmay include, for example, high energy radiation, thermal radiation,visible light, and combinations thereof. The composition of the presentinvention can also include free radical initiators. Such free radicalinitiators can include, for example, a peroxide or an azo compound.Preferably, a crosslinking agent used in the present invention is a freeradical initiator, such as, for example, 2,2′-Azobis(N,N′dimethyleneisobutyrarnidine) dihydrochloride or benzoyl peroxide.

In the present invention, the composition is crosslinked in an organicmedium, as set forth above. Furthermore, once crosslinked, the copolymercomposition is able to form a hydrogel upon exposure to a humidenvironment. As set forth above, such hydrogels are polymeric materialsthat swell in water without dissolving and that retain a significantamount of water in their structures while maintaining dimensionalstability. Such compositions have properties intermediate between thoseof liquids and solids. Hydrogels also deform elastically and recover,yet may flow at higher stresses. Hydrogel compositions of the presentinvention are less transient and can be controlled more easily thanknown non-crosslinked sealant compositions, as set forth previously.Thus, compositions of the present invention have distinct advantagesover known compositions and have superior functionality as sealants for,as an example, porous materials, particularly implantable medicaldevices, and as delivery devices for, as an example, therapeutic agents.

In one aspect of the invention, a therapeutic agent, such as, forexample, a drug or bio-active agent, can be introduced into thecopolymer composition of the present invention. The drug or bio-activeagent will be released in a controlled manner as the composition isbioresorbed. Thus, compositions of the present invention can be used todeliver therapeutic agents to specific sites in the body. Furthermore,such compositions can be engineered to bioresorb at particular rates byselecting the ratios of the bioresorbable regions to the hydrophilicregions as well as by controlling the degree of crosslinking and themolecular weight thereof. Thus, the present compositions are able todeliver controlled quantities of a therapeutic agent to a specific sitein the body as the hydrogel is bioresorbed.

Any drug or bio-active agent can be incorporated into a composition ofthe present invention provided that it does not interfere with therequired characteristics and functions of the composition. Examples ofsuitable drugs or bio-active agents include, for example, withoutlimitation, thrombo-resistant agents, antibiotic agents, anti-tumoragents, anti-viral agents, anti-angiogenic agents, angiogenic agents,anti-inflammatory agents, cell cycle regulating agents, their homologs,derivatives, fragments, pharmaceutical salts and combinations thereof.

Useful thrombo-resistant agents can include, for example, heparin,heparin sulfate, hirudin, chondroitin sulfate, dermatan sulfate, keratinsulfate, lytic agents, including urokinase and streptokinase, theirhomologs, analogs, fragments, derivatives and pharmaceutical saltsthereof.

Useful antibiotics can include, for example, penicillins,cephalosporins, vancomycins, aminoglycosides, quinolones, polymyxins,erythromycins, tetracyclines, chloramphenicols, clindamycins,lincomycins, sulfonamides, their homologs, analogs, fragments,derivatives, pharmaceutical salts and mixtures thereof.

Useful anti-tumor agents can include, for example, paclitaxel,docetaxel, alkylating agents including mechiorethamine, chlorambucil,cyclophosphamide, melphalan and ifosfamide; antimetabolites includingmethotrexate, 6-mercaptopurine, 5-fluorouracil and cytarabine; plantalkaloids including vinblastine, vincristine and etoposide; antibioticsincluding doxorubicin, daunomycin, bleomycin, and mitomycin; nitrosureasincluding carmustine and lomustine; inorganic ions including cisplatin;biological response modifiers including interferon; enzymes includingasparaginase; and hormones including tamoxifen and flutamide; theirhomologs, analogs, fragments, derivatives, pharmaceutical salts andmixtures thereof.

Useful anti-viral agents can include, for example, amantadines,rimantadines, ribavirins, idoxuridines, vidarabines, trifluridines,acyclovirs, ganciclovirs, zidovudines, foscarnets, interferons, theirhomologs, analogs, fragments, derivatives, pharmaceutical salts andmixtures thereof.

In another aspect of the present invention, there is provided a medicaldevice having associated with at least one surface thereof abioresorbable coating composition of the present invention. This coatingcomposition includes a hydrogel which is formed from the crosslinking ofa polymer containing a bioresorbable region, a hydrophilic region, aplurality of crosslinked functional groups, and, optionally, acrosslinking agent, as set forth previously.

In particular, the present bioresorbable coating compositions areintended to coat medical devices made from implantable materials. Thesebioresorbable coatings are capable of rendering porous medical devices,such as conduits, vascular grafts, textile materials, polymeric films,and the like, substantially impermeable to fluid. For purposes of thepresent invention, “substantially impermeable to fluid” refers to thespecific porosity of a material, such as a porous vascular orendovascular graft. Porosity of textile materials is often measured witha Wesolowski Porosity tester. With this apparatus, a graft is tied offat one end and the free end is attached to a valve on a porometer sothat the graft hangs freely in a vertical position. Then, water is runthrough the graft for one minute and the water that escapes from thegraft is collected and measured. The specific porosity of the graft isthen calculated according to the following formula: $P = \frac{V}{A}$

where V is the volume of water collected in ml/min and A is the surfacearea of the graft exposed to water in cm². A specific porosity of ≦1.0ml/min/cm² is considered an acceptable amount of leakage for animplantable vascular graft. Accordingly, for purposes of this invention,a substantially fluid-impermeable graft is defined as a graft with aspecific porosity, after impregnation with a sealant of the presentinvention, of ≦1.0 ml/min/cm². Porosities meeting and exceeding theacceptable specific porosity criteria set forth above can be achievedthrough the use of certain block copolymers described herein havingpolyether-polyester segments.

Implantable materials which can be used in the present invention caninclude, for example, polymeric materials, non-polymeric materials, andcombinations thereof The polymeric materials can include, for example,olefin polymers, including polyethylene, polypropylene, polyvinylchloride, polytetrafluoroethylene, fluorinated ethylene propylenecopolymer, polyvinyl acetate, polystyrene, poly(ethylene terephthalate),polyurethane, polyurea, silicone rubbers, polyamides, polycarbonates,polyaldehydes, natural rubbers, polyester copolymers, styrene-butadienecopolymers and combinations thereof. Non-polymeric implantable materialscan include, for example, ceramics, metals, inorganic glasses, pyrolyticcarbon and combinations thereof. The implantable materials set forthabove are intended to be exemplary only and should not be construed inany way to limit the types of materials which may be used in the presentinvention.

As set forth above, the implantable materials may be used in the presentinvention can be used to manufacture medical devices, such as forexample, endoprostheses. Grafts, stents and combination graft-stentdevices are contemplated. Preferably, these medical devices are vascularor endovascular grafts. Useful vascular or endovascular grafts includethose which are knitted, braided or woven, and can have velour or doublevelour surfaces. Alternatively, the medical device can be manufacturedfrom an extruded polymer, such as polytetrafluoroethylene (PTFE),particularly expanded polytetrafluoroethylene (ePTFE), polyethyleneterephthalate (PET), fluorinated ethylene propylene copolymer (FEP),polyurethane, silicone and the like. Composite structures are alsocontemplated.

In another preferred aspect, a medical device of the present inventioncan be a catheter, a guidewire, a trocar, an introducer sheath, or thelike. When coated onto such devices, the composition of the presentinvention imparts increased bio-compatibility to one or more surfacesthereof. Furthermore, when the composition of the present inventionincludes a drug or bio-active agent, specific therapeutic effects can beimparted to the surfaces of such devices. Moreover, the hydrophilicregion of the polymer composition of the present invention can impartincreased lubriciousness to the surfaces of, for example, a guidewire orother similar device.

Thus, any medical device to which the bioresorbable coating compositionof the present invention can adhere may be used for purposes of thepresent invention. Accordingly, the examples of implantable materialsand medical devices set forth above are for purposes of illustrationonly and are not intended to limit the scope of the materials anddevices to which the present bioresorbable coatings can be applied orotherwise associated therewith.

In another aspect of the present invention, pre-crosslinked andpost-crosslinked polymers of the present invention can be used in tissueengineering applications as supports for cells. Appropriate tissuescaffolding structures are known in the art, such as the prostheticarticular cartilage described in U.S. Pat. No. 5,306,311, the porousbiodegradable scaffolding described in WO 94/25079, and theprevascularized implants described in WO 93/08850 (all herebyincorporated by reference herein). Methods of seeding and/or culturingcells in tissue scaffoldings are also known in the art, such as thosemethods disclosed in EPO 422 209 B1, WO 88/03785, WO 90/12604, and WO95/33821 (all hereby incorporated by reference herein). Additionally,the cross-linkable prepolymers of the present invention can be used toencapsulate cells for tissue engineering purposes.

In another aspect of the present invention, there is provided a processfor forming a hydrogel. This process includes: (1) providing an organicsolution of a water-insoluble copolymer which contains a bioresorbableregion, a hydrophilic region, a plurality of cross-linkable functionalgroups per polymer chain, and, optionally, a crosslinking agent, and (2)effecting a crosslinking reaction, as set forth previously, and (3)exposing the composition to a humid environment to form a hydrogel,where steps (2) and (3) do not have to be carried out in any particularorder. In this process, the cross-linkable functional groups can be, butare not limited to, olefinically unsaturated groups. As set forthpreviously, the crosslinking agent can be a free radical initiator, suchas an azo or a peroxide compound. Still further, the crosslinkingreaction can be, for example, thermally or photochemically affected. Thehydrogel is formed when the copolymer composition is exposed to a humidenvironment.

In yet another aspect of the present invention, there is provided aprocess for forming a medical device coated with a hydrogel. Thehydrogel may be formed by a process as set forth above. The polymercomposition may be introduced into the medical device and subsequentlycrosslinked. Alternatively, the polymer composition may be crosslinkedprior to being introduced into the medical device. Once crosslinked, thepolymer composition may form a hydrogel when exposed to a humidenvironment.

The crosslinking agent can be activated in both humid and non-humidenvironments. In some instances, it is preferred that the activationtake place in a humid environment. In these cases, the hydrogel isformed directly. Preferably, the humid environment contains from about20% to about 100% water. More preferably, the humid environment containsfrom about 60% to about 100% water. In cases where the crosslinking iseffected in non-humid environments, the hydrogel is formed uponsubsequent exposure of the crosslinked copolymer to a humid environment.

The hydrogels formed by the above process can be packaged and stored ina variety of ways. For example, the hydrogel can be maintained in ahydrated state for an extended period of time. Alternatively, thehydrogel can be dehydrated and stored in an essentially desiccated stateuntil use, since the hydration and dehydration of these crosslinkedcopolymers is completely reversible. Furthermore, plasticizers can beadded to the dehydrated materials to provide materials with increasedflexibility. Plasticizers useful in this application include, but arenot limited to, glycerol, propylene glycol, and triethyl citrate.

Certain copolymer compositions of the present invention are liquids andcan be crosslinked in the absence of any solvent. When this solvent-freeprocess is employed, the hydrogel is formed upon subsequent exposure ofthe crosslinked copolymer to an aqueous environment.

The following examples are set forth to illustrate the copolymercompositions of the present invention. These examples are provided forthe purpose of illustration only and are not intended to be limiting inany sense.

EXAMPLE 1 Synthesis of lac-[peo/ppo]-lac Copolymer

Preparation of (Polymer A) According to the Present Invention wasSynthesized as Follows:

100.46 gm poly(ethylene-glycol)-co-poly(propyleneglycol)-co-poly(ethylene glycol) (75 wt % ethylene glycol, Mn=12,000)was charged to a 500 ml 4-neck reaction flask equipped with a Dean-Starkwater trap, a water-cooled condenser, a thermometer, and a gasinlet/outlet system which allowed for the controlled flow of nitrogen.While maintaining a nitrogen atmosphere, 230 ml of anhydrous toluene wasadded to the flask, the mixture was heated, and reflux was maintainedfor approximately 1 hour. During this period, any water present wascollected in the Dean-Stark water separator (approximately 30 ml of theoriginal toluene was also removed during this azeotropic water removal).The flask was allowed to cool to room temperature and 45.5 gmD,L-lactide was added to the flask along with 605 mg zinc lactate(monohydrate) catalyst. The reaction mixture was heated to reflux for16, hours during which time an additional 30 ml of toluene and wasremoved via the Dean-Stark water separator. 4.00 gm of triethylamine wasadded to the reaction mixture at room temperature, and, after 5 minutesof stirring, 3.34 gm of acryloyl chloride was slowly added to the flask.The mixture was then stirred at room temperature for 5.0 hours.Approximately 110 mg of 4-methoxy phenol was added to the flask as afree-radical inhibitor. The solution was then transferred to largecentrifuge bottles and solid by-products were removed via centrifugationat 5° C.@9000 rpm followed by decantation of the clear supernatantsolution. This solution was then reduced in vacuuo on a rotaryevaporator at 60° C.@<25 mm Hg until all traces of solvent and othervolatile materials were removed. The polymer thus prepared and isolatedwas a water-insoluble, viscous liquid at room temperature.

EXAMPLE 2 Synthesis of lac-[peo/ppo]-lac Copolymer

Preparation of (Polymer B) According to the Present Invention wasSynthesized as Follows:

100.46 gm poly(ethylene-glycol)-co-poly(propyleneglycol)-co-poly(ethylene glycol) (75 wt % ethylene glycol, Mn=12,000)was charged to a 500 ml 4-neck reaction flask equipped with a Dean-Starkwater trap, a water-cooled condenser, a thermometer, and a gasinlet/outlet system, which allowed for the controlled flow of nitrogen.While maintaining a nitrogen atmosphere, 230 ml of anhydrous toluene wasadded to the flask, the mixture was heated to reflux, and reflux wasmaintained for approximately I hour. During this period, any waterpresent was collected in the Dean-Stark water separator (approximately30 ml of the original toluene was also removed during this azeotropicwater removal). The flask was allowed to cool to room temperature and71.44 gm D,L-lactide was added to the flask along with 605 mg zinclactate.(monohydrate) catalyst. The reaction mixture was heated toreflux for 16 hours, during which time an additional 30 ml of tolueneand was removed via the Dean-Stark water separator. 4.00 gm oftriethylamine was added to the reaction mixture at room temperature,and, after 5 minutes of stirring, 3.34 gm of acryloyl chloride wasslowly added to the flask. The mixture was then stirred at roomtemperature for 5.0 hours. Approximately 110 mg of 4-methoxy phenol wasadded to the flask as a free-radical inhibitor. The solution wastransferred to large centrifuge bottles and solid by-products wereremoved via centrifugation at 5° C.@9000 rpm followed by decantation ofthe clear supernatant solution. This solution was then reduced in vacuuoon a rotary evaporator at 60° C. @<25 mm Hg to remove all solvent andother volatile materials. The polymer thus prepared and isolated was awater-insoluble, viscous liquid at room temperature.

EXMPLE 3 Synthesis of lac-[peo/ppo]-lac Copolymer

Preparation of (Polymer C) According to the Present Invention wasSynthesized as Follows:

96.65 gm poly(ethylene-glycol)-co-poly(propyleneglycol)-co-poly(ethylene glycol) (75 wt % ethylene glycol, Mn=12,000)was charged to a 500 ml 4-neck reaction flask equipped with a Dean-Starkwater trap, a water-cooled condenser, a thermometer, and a gasinlet/outlet system which allowed for the controlled flow of nitrogen.While maintaining a nitrogen atmosphere, 230 ml of anhydrous toluene wasadded to the flask, the mixture was heated to reflux, and reflux wasmaintained for approximately 1 hour. During this period, any waterpresent was collected in the Dean-Stark water separator (approximately30 ml of the original toluene was also removed during this azeotropicwater removal). The flask was allowed to cool to room temperature and54.71 gm D,L-lactide was added to the flask along with 605 mg zinclactate (monohydrate) catalyst. The reaction mixture was heated toreflux for 16 hours, during which time an additional 30 ml of tolueneand was removed via the Dean-Stark water separator. 4.00 gm oftriethylamine was added to the reaction mixture at room temperature,and, after 5 minutes of stirring, 3.34 gm of acryloyl chloride wasslowly added to the flask. The mixture was then stirred at roomtemperature for 5.0 hours. Approximately 110 mg of 4-methoxy phenol wasadded to the flask as a free-radical inhibitor. The solution wastransferred to large centrifuge bottles and solid by-products wereremoved via centrifugation at 5° C.@9000 rpm followed by decantation ofthe clear supernatant solution. This solution was then reduced in vacuuoon a rotary evaporator at 60° C.@<25 mm Hg to remove all solvent andother volatile materials. The polymer thus prepared and isolated was awater-insoluble, viscous liquid at room temperature.

EXAMPLE 4 Crosslinking of the Above Polymers in an Organic Solvent or anOrganic/aqueous Solvent System and Physical Characterization of theResulting Materials

Preparation and Testing of Crosslinked Polymer Systems.

Each of the solutions described below was transferred to a shallowTeflon™ mold (9.0 cm×9.0 cm×1.0 cm) and sparged with argon to removeoxygen from the solution. The filled molds were then sealed with glasscover plates and heated in an oven for the duration and temperaturesdescribed below.

Solution 1 (Composition D)

To a solution of 15 wt % polymer A (prepared in Example 1) in 75:251-propanol/water was added Vazo 044™ initiator (20 mg/1.00 gm polymer).Solution was cured in a mold as described above for 6 hours at 75° C.

Solution 2 (Composition E)

To a solution of 30 wt % polymer C (prepared in Example 3) in anhydrous1-propanol was added benzoyl peroxide (60 mg/1.0 gm polymer). Solutionwas cured in a mold as described above for 4 hours at 60° C.

Solution 3 (Composition F)

To a solution of 15 wt % of Polymer C (prepared in Example 3) in 50:501-propanol/water was added 2,2′-Azobis (N,N′-dimethyeneisobutyramidine)dihydrochloride [Vazo-44™], (40 mg/100 gm polymer). Solution was curedin a mold as described above for 4 hours at 60° C.

The resulting crosslinked compositions D, E and F were de-molded, washedthree times in deionized water and three times in 1-propanol, and driedin vacuuo to afford small sheets of crosslinked polymer compositions.The compositions D, E and F thus obtained were flexible at roomtemperature and exhibited good elastic recovery when deformed. Whenexposed to aqueous environments, the compositions D, E and F absorbedwater rapidly to afford dimensionally stable hydrogels.

Dumbbell-shaped tensile test specimens (length=38 mm, width at center=5mm, width at ends=16 mm) were die cut from the above composition andstress-strain properties were determined on an Instron™ tensile testerusing a uniaxial pull with a cross-head speed of 8.0 in/min and adistance of 1.0 in between grips. Results of this testing is shown inTable 1.

TABLE 1 Tensile Strength Elongation at Break Composition (lb/in²) (%) D242 1474 E 199 1270 F 270 1557

EXAMPLE 5 Procedure for Determination of Water-solubility of Polymers

In a large centrifuge bottle, 2.0±0.2 gm of polymer was dispersed in200.0±5.0 ml of distilled water by manual agitation for 20 minutesfollowed by 5 minutes of agitation in an ultrasonic bath, all at roomtemperature. This dispersion was then centrifuged at 9,000 rpm for 30minutes, resulting in a clean separation onto an upper polymer phase anda lower polymer phase. A 125 ml aliquot of this upper aqueous layer wascarefully removed via aspiration so as not to disturb the lower polymerphase. This 125 ml aliquot was lyophilized to afford a small quantity ofextracted material. The % water-solubility of the polymer was calculatedas follows:

 % solubility in water=(weight of extracted material/original weight ofpolymer)×100

or

solubility (grams/100 ml)=(weight of extracted material in grams)×(100ml/125 ml)

As measured according to this procedure, the polymers of the examplespresented have water solubility in the range of 0.012 to 0.058 gm/ 100ml.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A composition comprising an organic solution of awater-insoluble copolymer having (1) a bioresorbable region; (2) ahydrophilic region; and (3) a plurality of cross-linkable functionalgroups per polymer chain of the following general formula:

wherein x is from about 10 to about 100 and y is from about 50 to about500, and a substantially non-aqueous organic solvent.
 2. The compositionof claim 1, wherein said water-insoluble copolymer has the followinggeneral formula:

wherein the ratio of A to B is about 3:1, x is from about 10 to about100, and y is from about 50 to about 300, so long as the compositionremains substantially water-insoluble as a whole.
 3. The composition ofclaim 1, wherein said water insoluble copolymer is selected from thegroup consisting of di-block copolymers, tri-block copolymers, and starcopolymers.
 4. The composition of claim 1, wherein said tri-blockcopolymer has the general formula: xABAx wherein A is the bioresorbableregion, B is the hydrophilic region, and x is the cross-linkablefunctional group.
 5. The composition of claim 1, wherein said organicsolution further comprises a mixture of an organic solvent and up to 50%water.
 6. The composition of claim 1, wherein said solvent is selectedfrom the group consisting of aliphatic and aromatic alcohols.
 7. Thecomposition of claim 1, wherein said bioresorbable region is selectedfrom the group consisting of poly(esters), poly(hydroxy acids),poly(lactones), poly(amides), poly(ester-amides), poly(amino acids),poly(anhydrides), poly(ortho-esters), poly(carbonates),poly(phosphazines), poly(thioesters), polysaccharides and mixturesthereof.
 8. The composition of claim 1, wherein said hydrophilic regionis selected form the group consisting of polyethers, polyalkyleneoxides, polyols, poly(vinylpyrrolidine), poly(vinyl alcohol), poly(alkyloxazolines), polysaccharides, carbohydrates, peptides, proteins, andcopolymers and mixtures thereof.
 9. The composition of claim 1, whereinsaid bioresorbable region is hydrophilic.
 10. The composition of claim1, wherein said bioresorbable region has hydrophilic character withoutrendering the polymer water-soluble.
 11. The composition of claim 1,wherein said hydrophilic region forms an excretable and/or metabolizablefragment.
 12. The composition of claim 1, wherein said plurality ofcross-linkable functional groups are olefinically unsaturated groups.13. The composition of claim 1, wherein said composition furtherincludes a free radical initiator.